Disease factors of dietary, chemical and genetic origin can seriously interfere with brain function. The exposure of brain tissue to such factors during development may impair formation of myelin. On the other hand, exposure of the brain to dietary or environmental changes in adult life, can result in demyelination. It is presumed that these factors produce their pathogenic effects by interfering with one or more enzymatic reactions involved in the metabolism of myelin lipids. The purpose of this research project is to define myelin and EEG abnormalities in animal model(s) of phenylketonuria, a disease which is associated with retarded brain function. We expect, 1) to determine exactly what kinds of disorders in brain lipid metabolism are found in experimental hyperphenylalaniemia, 2) to specify the reactions of lipid metabolism that are implicated, 3) to determine the mechanism of their inhibition, and 4) to determine if the disorders in lipid metabolism can be overcome. To examine the functional impact of these impairments in myelin metabolism, we plan to study EEG abnormality in experimental hypo- and de-myelinating conditions. Cerebral potentials evoked to acoutic stimuli (auditory evoked potentials, AER) and arising from structures extending from the brainstem to the cortex have proven to be relatively stable measures of neuronal activity in these parts of the brain. Characteristic changes in the latencies and amplitude of these potentials occur during maturation and may be disrupted by dietary, chemical or environmental changes. We plan to determine EEG abnormalities in developing hyperphenylalaninemic animals, and in adult rats exposed to agents which are known to induce specific myelinopathy in the nervous system.